Traditional models of schizophrenia have focused on dopaminergic systems. More recent models, however, derive from the phencyclidine (PCP, xe2x80x9cangel dustxe2x80x9d) model of schizophrenia (Javitt, 1987; Javitt and Zukin, 1991) and postulate that schizophrenia is associated with dysfunction or dysregulation of neurotransmission mediated at brain N-methyl-D-aspartate (NMDA)-type glutamate receptors. The PCP/NMDA model of schizophrenia raised the possibility that agents which augment NMDA receptor-mediated neurotransmission might be therapeutically beneficial in schizophrenia. The primary neurotransmitter acting at NMDA receptors is glutamate. However, NMDA receptor activity is also modulated by the amino acid glycine which binds to a selective modulatory site that is an integral component of the NMDA receptor complex. U.S. Pat. No. 5,854,286 discloses the use of orally administered glycine, in dietary quantities, for the treatment of schizophrenia.
Glycine is considered a full agonist at the NMDA-associated glycine binding site (McBain et al., 1989). The clinical findings with glycine detailed in the prior patents U.S. Pat. No. 5,854,286 and U.S. Pat. No. 5,837,730 applications therefore, provided the first evidence that glycine-site full agonists are effective in the treatment of schizophrenia. This concept has also recently been supported by a study utilizing D-serine (Tsai et al., 1998), an alternative glycine site full agonist (McBain et al., 1989; Javitt et al., 1989; Kleckner and Dingledine, 1988; Wong et al., 1987; Reynolds et al., 1987), consistent with the ability of this compound to induce glycine-like behavioral effects in rodents (Tanii et al., 1994, 1991) and to penetrate into CNS following peripheral administration (Hashimoto and Oka, 1997). D-Serine, like glycine, is present in brain in high concentration and may serve as an endogenous ligand for the glycine binding site of the NMDA receptor complex (Schell et al., 1995). The use of D-serine, along with use of other agents that might substitute for glycine at the glycine site of the NMDA receptor complex, was disclosed in the above noted U.S. patents and in Provisional application 60/008361 filed Dec. 1, 1995.
Although the findings with glycine and D-serine support the use of full glycine-site agonists, others have proposed that partial agonists at the glycine site, such as the drug D-cycloserine, should be more effective than full agonists in the treatment of schizophrenia (Cordi, patent No. 5,187,171). Partial agonists bind to the same site as full agonists (i.e., glycine recognition site of the NMDA receptor complex), but potentiate channel opening only to a much smaller percent (typically 40-70% of the activation seen with full agonists, McBain et al., 1989). Clinical studies with D-cycloserine have provided support for the concept that partial glycine-site antagonists may be effective in the treatment of schizophrenia (reviewed in D""Souza et al., 1995), and, the degree of improvement seen in studies of D-cycloserine (reviewed in D""Souza et al., 1995) has been comparable in some circumstances to the degree of improvement observed following studies with glycine (Heresco-Levy et al., 1996; Leiderman et al., 1996 and reviewed in D""Souza et al., 1995) or D-serine (Tsai et al., 1998). No study has yet compared the effectiveness of glycine treatment to that of D-cycloserine treatment.
A second potential approach to augmentation of NMDA receptor-mediated neurotransmission is the administration of agents that inhibit glycine transporters in brain, thereby preventing glycine removal from active sites within CNS. It has been known for many years that the brain contains active transport systems for glycine that may regulate brain levels (Debler and Lajtha, 1987; D""Souza, 1995). More recent studies demonstrated that glycine transporters are differentially expressed in different brain region (Liu et al, 1993; Zafra et al., 1995) and may be co-localized with NMDA receptors (Smith et al., 1992). However, it has also been known for many years that extracellular glycine levels are beyond the level needed to saturate the NMDA-associated glycine binding site, making it unclear whether glycine transporters are, in fact, able to maintain subsaturating glycine levels in the immediate vicinity of NMDA receptors. This is a crucial issue in that, if glycine levels were already at or above saturating levels, additional glycine would not, on theoretical grounds, be able to stimulate NMDA functioning (Wood, 1995).
U.S. Pat. No. 5,837,730, to the current inventor provided the first evidence that an identified glycine transport inhibitor, glycyldodecylamide (GDA), was able to exert glycine-like, anti-PCP behavioral effects in rodents, and thus the first evidence that glycine transport inhibitors should exert glycine-like amelioration of negative and cognitive symptoms in schizophrenia. In U.S. Pat. No. 5,837,730, data were presented from a series of three compounds demonstrating appropriate rank order of potency of these compounds in producing glycine-like behavioral effects in rodents.